Background: Lung cancer chemoprevention is an important concept to reduce lung cancer incidence and thus lung cancer related mortality. Most chemoprevention approaches so far have either resulted in negative or even harmful results. The role of epigenetic alterations in non-small cell lung cancer is well established. We have exciting preliminary data that lung cancer risk is substantially decreased in US veterans with long term use of the HDAC-Inhibitor valproate compared to controls which were matched by age and diagnosis (HR 0.63; 95%CI 0.51-0.74). In addition, we have in-vitro data that valproate has far further reaching epigenetic effects than merely upregulation of acetylated histones. Specifically, we also observe induction of the H3K4m2- 3 activating histone mark and downregulation of the DNAmethyltransferase (DNMT1) and the histone H3K9 methyltransferase G9A, together with a reduction in anchorage independent colony formation in soft-agar. We hypothesize that due to its direct and indirect epigenetic effects valproate can a) permanently reverse and b) prevent oncogenic transformation in bronchial epithelial cells. The study has three specific aims: #1: To determine the underlying mechanisms of HDAC-I mediated prevention and reversal of bronchial epithelial cell transformation and to study associated changes in histone modifications at individual gene levels #2: To determine the effects of HDAC-inhibition on genome-wide patterns of DNA methylation and H3K9me3- marks in carcinogen transformed cells. #3: To determine if HDAC-I exposure can reverse DNA methylation in the sputum of high-risk subjects for lung cancer Significance: Should HDAC inhibition, as hypothesized, truly permanently reverse oncogenic transformation, this will be a major milestone, since no other chemopreventive strategy has been show to have that effect so far. In this case, valproate would in fact be an ideal chemopreventive agent since it would allow to reset the epigenetic clock to a pre-transformed phenotype and it would alleviate the need for patients at risk to stay on life-long therapy. Preliminary data of our population study in US veterans strongly supports HDAC inhibition as a clinically active chemoprevention strategy in lung cancer. With a 37% absolute risk reduction for lung cancer incidence, this would translate into 55,000 lives saved per year.